1. Field of the Invention
This invention relates to a gene therapy for neoplasm, wherein a tumor cell is trasnduced with a gene encoding a soluble costimulatory factor. The transduced tumor cell secretes the costimulatory factor which induces T-cells to attack both transduced and untransduced cells of the tumor.
2. Description of the Related Art
The induction of an antigen-specific immune response requires three distinct interactions between antigen presenting cells (APCs) and antigen. The first interaction is adhesion, where APCs and T-cells randomly interact by adhesion molecules, which are cell surface ligands and their respective receptors. The second interaction, recognition, will occur if the APCs can process, transport, and present sufficient quantities of the antigen within a major histocompatibility complex (MHC) molecule. The antigen-MHC is then recognized by the T-cell via the ligation (i.e., binding and cross-linking) of the T-cell receptor complex (TCR) to the antigen-MHC. The third interaction, costimulation, is needed for T-cells to induce cellular proliferation, cytokine secretion, and effector function. The second and third interactions are respectively known as signal 1 and signal 2. If signal 2 is not delivered, T-cells enter anergy, a state of long-term unresponsiveness to specific antigens.
Induction of tumor-specific cytotoxic T lymphocytes (CTL) requires the two signals noted above to be present on APCs. The first signal is a tumor antigen, which is processed, transported to, and presented by MHC class I and/or class II molecules on the surface of APCs. The second signal is a costimulatory molecule present on tumor cells and/or other APCs (Mueller et al., 1989, Annu. Rev. Immunol. 7:445–480). Anergy or tolerance to tumor cells occurs as a result of CD8+ T-cells receiving the signal of a MHC-bound tumor antigen, but not a second signal of costimulatory molecules (Schwartz, 1993, Sci. Am. 269:48–54).
Membrane proteins of the B7 family are known to be the most potent of the costimulatory molecules (Galea-Lauri et al., 1996, Cancer Gene Ther. 3:202–213). However, the expression of a single costimulatory factor on the tumor cell membrane is ineffective in nonimmunogenic tumors, presumably due to the lack of coexpression of MHC-bound tumor antigen (Chen et al., 1994, J. Exp. Med. 179:523–532).
The environment where an immune response is initiated can influence which types of cells become antigen presenting cells. In the peripheral blood, for example, dendritic cell, activated B cells, and monocytes serve as antigen presenting cells, whereas in the skin, keratinocytes and Langerhans cells present antigens. “Professional” APCs are cells such as dendritic cells, activated B cells, and activated macrophages, which can process and present antigens on their surface. Professional APCs have been found to have the ability to present tumor antigens in association with an MHC molecule. Tumor cells also can serve as APCs.
Huang et al. (1994, Science, 264:961–965) have found that MHC class I-restricted tumor antigens usually are not presented by the tumor itself, but by dendritic cells or bone-marrow-derived APCs. Dendritic cells are capable of efficiently presenting antigen derived from apoptotic cells or virus-infected cells, stimulating class I-restricted CD8+ CTLs (Albert et al., 1998, Nature, 392:86–89). Dendritic cells that infiltrate tumors, however, can lack B7 molecules and therefore have reduced T-cell stimulatory activity (Chaux et al., 1996, Lab. Invest., 74:975–983).
Current gene therapies aimed at the control of cancer often fail because none of the current gene vectors are capable of infecting 100% of the cells of a tumor. Consequently, these therapies do not result in total destruction of the tumor.